Cholesterol is commonly found in all the tissues and blood of mammals, especially humans. Manufactured in the liver and other cells as a substrate for other steroids and membrane synthesis; cholesterol is a normal constituent of bile. As will be appreciated, many familiar foods contain cholesterol, with some containing more than others. Maintaining proper levels of cholesterol in the body has become an important factor in todays diet, since medical science has proven that certain afflictions such as hypothyroidism, diabetes and the intake of foods having a high cholesterol content may result in high levels of cholesterol in the blood.
A condition which is associated with elevated levels of cholesterol, phospholipids, and/or triglycerides in the blood serum of mammals is commonly referred to as hyperlipidemia (i.e. as used herein, reference to hyperlipidemia is intended to be inclusive of both hypercholesterolemia and hypertriglyceremia, and hence, compounds having a hypolipidemic effect will exhibit activity to lower both cholesterol and triglyceride lipid levels). Hyperlipidemia can lead to serious health problems such as arthereosclerosis. We know that serum lipoprotein in mammals is composed of cholesterol together with triglyceride, phospholipid and apoproteins. Lipoprotein is composed of several fractions--the very low density lipoprotein (VLDL), the low density lipoprotein (LDL) and the high density lipoprotein (HDL) depending on the specific gravity of the apoprotein components of the fraction. Medical evidence points to the VLDL and LDL fractions as being associated with atherosclerosis. In contrast, the HDL fraction appears to carry cholesterol from the blood vessels to the liver where it is processed and excreted in the bile. As hyperlipidemic states increase in atherosclerosis the LDL cholesterol increases and HDL decreases. Effective hypolipidemic agents need to reverse this ratio since clinical data indicate that high HDL cholesterol and low LDL cholesterol protects man from myocardial infarctions. Thus, it is highly desirable to treat mammals afflicted with hyperlipidemia so as to lower VLDL and LDL fractions and increase the HDL fractions.
It is not surprising to find that a number of compounds have been proposed for the treatment of hyperlipidemia in mammals. Examples include U.S. Pat. No. 4,499,303 which describes the use of a novel class of N-benzoylsulfamates and benzoylsulfonamides as useful hypolipidemic agents. U.S. Pat. No. 4,395,417 proposes the use of cyclic imides, diones, reduced diones and analogs as useful agents. Orotic acid has been shown to decrease the plasma lipids blood level in rats.
U.S. Pat. No. 4,639,444 describes 3,5-dialkyl-4,6-diaryltetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives as useful hypolipidemic agents. U.S. Pat. No. 4,681,893 teaches that certain trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and their ring opened acids are potent hypolipidemic agents. Likewise, U.S. Pat. No. 4,351,844 describes hypocholesterolemic lactone compound and their free acids which are derived from the natural fermentation product mevinolin. More recently, the control of hyperlipidemia through the use of a class of 4-pyrimidinecarboxylic acids has been described by Hall et al., J. Pharm. Sci. 74, 759 (1985).
In spite of the numerous compounds and methods which have been proposed for the control of hyperlipidemia, the need remains for drugs having enhanced lowering of elevated serum lipoprotein lipids.
Accordingly, it is the object of the present invention to provide a class of hypolipidemic compounds having enhanced capability in lowering LDL cholesterol and elevating HDL cholesterol. This and other objects of the present invention will be more apparent from the discussion which follows.